Process for oxidation of heterocyclic nitrogen compounds



Patented Feb. 4, 1947 rnocnss roaoxma'rron or unmocrcmo-m'rnocnn COMPOUNDS 1,

James Ogilvie, Buflalo, and Alvin .i. sweet, East Aurora, N. Y., assi gnors to Allied Chemical &

Dye Corporation, New York, N. Y., a corporatlon of New York No Drawing. Application August 27, 1942,

Serial No. 456,368

6 Claims. (Cuzco-295.5)

This invention relates to the oxidation of heterocyclic nitrogen compounds containing a pyridine nucleus substituted by'an oxidizable organic especially when practiced on a large scale; furgrouping attached to the nucleus by one or more carbon-to-carbon linkages and capable of being I oxidized to a carboxylic group, so as to produce a carboxyllc acid, more particularly to the production of nicotinic acid from beta-substituted Pyridine compounds.

The present need of plentiful supplies of the vitamin B complex for proper nutritional requirements has greatly increased the importance of producing nicotinic acid, a member of the vitamin B complex. It is known that nicotinic acid can be prepared by oxidation of beta-picoline (B-methyl pyridine) with an aqueous permanganate solution, nitric acid, or a solution of chromic acid in sulfuric acid. However, none of these processes is satisfactory becaus they are relatively diilicult to operate and result in poor yields of nicotinic acid. The processes which utilize strong acids such as nitric or sulfuric acid present substantial corrosion problems which must be overcome by the use of special equipment; furthermore, the -use of acid oxidizing media generally tends to cause the nicotinic acid to precipitate from the reaction mixture in association with contaminating insoluble reaction products which render recovery of the nicotinic acid in pure form somewhat diflicult. As a result there is a great demand for a simple and efiective process for the manufacture, particularly on a mainder of the reaction mixture, and recovery of nicotinic acid therefrom, for example, by converting the copper nicotinate to sodium nicotinate by treatment with sodium hydroxide and acidifying the resulting sodium nicotinate, or by t reacting the copper nicotinate with hydrogen sulfide, whereby copper sulfide and nicotinic acid are produced. However, formation of copper nicotinate and its subsequent separation from adhering impurities is expensive and troublesome,

thermore, when'nicotinic acid is recovered from copper nicotinate by treatment with hydrogen ,sulflde; the resulting product is almost always contaminated with sulfur impurities which are extremely undesirable in a product to be used for therapeutic purposes.

- It is an object of this invention to provide an improved process for the oxidation of heterocyclic nitrogen compounds containing a pyridine nucleus substituted by an oxidizable organic grouping attachedto the nucleus by one or more carbon-.to-carbon linkages.

A idore specific object of this invention is to provide a simple and practical process for the production of nicotinic acid from beta-picoline.

Another object of this invention is to provide 7 an improved process for the recovery of nicotinic acid from aqueous reaction mixtures containing this material.

In accordance with this invention a heterocyclic nitrogen compound containing in its structure' a pyridine nucleus substituted by an oxidizable organic grouping attached to the nucleus by one or more carbon-to-carbon linkages, is oxidized to a carboxylic acid by treatment with a substantially neutral to alkaline aqueous solution of a water-soluble hexavalent chromium com-.

pound at a temperature of at least about C. and under a superatmospheric pressure equivalent to the vapor pressure of the reacting mixture atthe temperature employed. The desired carboxylic acid product remains in solution in the substantially neutral to alkaline reaction mixture, whereas the chromic oxide simultaneously produced precipitates therefrom and can be removed from the desired product substantially quantitatively by simple means such as filtration, thereby facilitating recovery of the carboxylic acid. The preferred embodiment of our invention involves oxidation of beta-picoline with a substantially neutral to alkaline aqueous solution of a watersoluble hexavalent chromium compound in a closed vessel at a temperature between about 200 and about 250 C. and under the superatmospheric pressure generated in the vessel at the temperature employed by vapors of the reacting mixture; by operating in accordance with this method, excellent yields of the highly valuable 'nicotiriic; acid may be have found, be recovered from-the reaction mixture in a simple and effective manner by reducing the pH value of the mixture toa point between readily obtained. Nicotinic *acid produced by our invention may, we

about 3 and about 4, preferably between about 3.2

tion mixture whereby nic otinic acid in substanwill be noted, avoids the complicated and expensive recovery method heretofor employed involving formation and separation of copper nicotinate a d thus greatly simplifies the problem of recovering thevaluable nicotinic acid. I

The oxidation procedure of our invention proceeds easily to form the desired carboxylic acid in excellent yields. Since the reaction is carried out in a substantially neutral to alkaline medium,

no corrosion problems are presented, so that specially constructed equipment need not be em-' ployed. In view thereof it is evident fourn'ovel and about'3.6, e. g. 3.3, and then cooling the-reac tially pure condition separates; this method, it v the reaction of the acid and the basicications; since alkali metal salts of. pyridine carboxylic acids are water-soluble, alkali metal salts of hexavalent chromium compounds are preferably employed. Some of the cromic acid salt maybe replaced by an equivalent amount of free chromic acid, but there should be a sufllcient amount of heterocyclic' nitrogen compound to be oxidized procedure provides a greatlysimplified oxidation process for the production of valuable pyridine carboxylic acids such as nicotinic acid.

As hereinabove pointed out, our'invention is applicable tov the oxidation of any heterocyclic nitrogen compound containing in its structurea pyridine nucleus substituted by an oxidizable organic grouping attached to the nucleus by one or more carbon-to-carbon linkages. Thus, for

example, the picolines, lutidines, collidines, quinoline and'its derivatives such as hydroxyquinolines and quinoline sulfonic acids, isoquinoline,

quinaldine, lepidine, and nicotine'may all be treated in accordancewith' our invention. The nature ofthe product obtained will vary, de

pending upon the particular compound treated.

Thus, for example, oxidation of beta-picoline or nicotine in accordance with this invention yields the highly valuable nicotinic acid; oxidation of alpha-picoline '(2-methyl pyridine) .yields piec linic acid; oxidation of gamma-picoline (4-methyl pyridine) yields isonicotinic acid. As hereinabove stated, a preferred embodiment of our invention involves the oxidation of beta-picoline since this compound is readilyavailable and at the present time the resulting product, i. e. nicotinic acid, is the most useful of the pyridine carboxylic acids. I

The hexavalent chromium compound employed as the oxidizing agent in accordance with our invention may be any one or a compatible mixture of'water-soluble hexavalent chromium compounds forming a substantially neutral to alkaline solution in water, but preferably one or more water-soluble salts of chromic acid such as the neutral chromates or polychromates are emdium, potassium and ammonium dichromate,

, have been found to be particularly suitable for preferably such that water-soluble salts of the pyridine carboxylic acid product are form d y ployed. Water-soluble dichromates, notably sothe presence of chromic acid. The basic cations present in the aqueous oxidizing solutions'are and the number of atoms of hexavalent chromium present. in the chromium compound employed. When operating in accordance with the preferred embodiment of our invention, 1. e., when oxidizing beta-picoline with an alkali metal dichromate, 1 mol of dichromate per mol of picoline is theoretically required for the oxidation, where-' as if a monochromate such as sodium chromate were employed, 2-mols of the hexavalent chromium compound per mol of beta-picoline would be theoretically required. We prefer to employ an amount of the hexavalent chromium compound equivalent to about 50% in excess of'the' theoretical quantity required for the oxidation,

since we have found optimum yields of the desired pyridine carboxylic acid may thereby be obtained.

In accordance with our invention the hetero- I cyclic nitrogen compound to be oxidized is mixed with the substantially neutral to alkaline oxidizing agents and the mixture maintained at a temperature of at least about 150 0;, preferably between 200" and 250 (3., and at a pressure equivalent to thevapor pressure of the reacting mixture at the temperature employed until the reaction has been substantially completed. The

pressure under which the reaction mixture is maintained may be in the neighborhoodof from about 5 to about atmospheres. Thus-for example, the reaction may be suitably carried out by disposing the reaction mixture in a high-pressure autoclave and heating the mixture in the autoclave to the desired elevated temperature.

The time required for the oxidation may vary but a time between about fifteen and about twenty hours, e. g. seventeen hours, is generally sufficient. In carrying out the reaction the mixture is preferably agitated by suitable agitating means in order to insure maximium contact of the reacting ingredients with one another.

The preferred embodiment of our invention, i. e. oxidation of beta-picoline with an alkali dichromate, may be performed by introducing the beta-picoline and an aqueous dichromate solution containing about 50% dichromate into an autoclave and heating the autoclave to a temperature between about 200 and about 250 0., preferably between about 220 and about 225 C., until oxidation of the beta-picoline has been substantially completed, which may require about seventeen hours. At-the end of thistime the reaction mixture may be cooled, the pressure re lieved and theinsoluble chromic oxide formed as aresult of the oxidation removed from the reaction mixture by filtration; the chromic oxide shouldbe washed to remove adhering reaction product, the washings being added to the filtrate.

The combined filtrate and washings may then be treated with barium chloride to removeexcess about 3.3; upon cooling the thus acidified solu-.

tion, it will be found, substantially pure nicotinic acid is obtained in excellent yields. The residual nicotinic acid remaining in the solution, whch usually amounts to less than 17% of the total product, may be recovered by the formation of copper nicotinate and conversion thereof to nicotinicacid or by evaporating the residue to dryness and extracting the mass with alcohol to remove the nicotinic acid.

The following example is illustrative of our invention. Amounts are given in parts by weight.

116 parts of beta-picoline, 500 parts of water and 563 parts of sodium dichromate dihydrate were introduced into an autoclave, and the mixture heated with strong agitation at a temperature between 220 and 225 C. for seventeen hours; the pressure within the autoclave during this time as recorded by a gauge was between 320 and 350 pounds per square inch. At the end of the heating period the reaction mass was permitted to cool and then filtered; the chromic oxide filter cake was washed with water, and

the washings were admixed with the filtrate.

The combined filtrate and washings were then boiled to remove traces of unreacted beta-picoline and 325 parts of barium chloride dihydrate dissolved in 550 parts of water were added to the boiling mass, the precipitated barium chromate being removed by filtration. To the filtrate, was added concentrated sulfuric acid until no further barium sulfate precipitate was formed; to the suspension was then added 10 parts of Filter Cell and 10 parts of animal charcoal, the mass agitated and then filtered. The filtrate was then made slightly alkaline to Clayton Yellow with sodium hydroxide and evaporated to a point such that the nicotine acid concentration was about 12%. The concentrated solution was then cooled to about 20 C. and 20 B. hydrochloric acid added thereto until the pH was reduced to 3.3. This solution was cooled to C. and the nicotinic acid crystals which formed were removed by filtration, washed and dried; the resulting product melted at 229 C. The mother liquor and wash water were combined, concentrated and cooled to about 70 C.; 50 parts of copper sulfate pentahydrate dissolved in 50 parts of water were added thereto and the mass permitted to stand at room temperature for about twelve hours. The copper nicotinate precipitate was removed by filtration, washed and suspended in about 200 parts of water; the suspension was made alkaline with sodium hydroxide and then boiled to preclpitate the copper as copper oxide. The oxide was removed by filtration and the filtrate acidified until its pH value was 3.3. This solution was then cooled to 0 C. and nicotinic acid which precipitated was recovered by filtration, washed and dried. Approximately 83% of the nicotinic acid product was recovered at the first crystallization step.

It will be evident from the above description that our invention provides an extremely useful method for the production of pyridine carboxylic acids, particularly the highly valuable nicotinic acid and, hence, will be of great interest to those ing sense.

engaged in the manufacture of such chemicals.

Since certain changes may be made in carrying out the above process without departing from the scope of the invention, it is intended that all matter contained in the above description shall be interpreted as illustrative and not in a limit- We claim:

1. A process for the oxidation of a heterocyclic nitrogen compound containing in its structure a pyridine nucleus substituted by an oxidizable organic grouping attached to the nucleus by one or more carbon-to-carbon linkages to a carboxylic acid, which comprises reacting said compound with a substantially neutral to alkaline aqueous acid, which comprises reacting said compound with a substantially neutral to alkaline aqueous solution of a water-soluble hexavalent chromium compound at a temperature between about 200 and about 250 C. and under a superatmospheric pressure equivalent to the vapor pressure of the reacting mixture at the temperature employed, separating the insoluble chromic oxide formed by the oxidation from the remainder of the reaction mixture, and recovering the carboxylic acid.

3. A process for the oxidation of beta-picoline to nicotinic acid which comprises reacting betaplcoline with a substantially neutral to alkaline aqueous solution of a water-soluble hexavalent chromium compound at a temperature between about 200 and about 250 C. and under a superatmospheric pressure equivalent to the vapor pressure of the reacting mixture at the temperature employed.

4. A process for the oxidation of beta-picoline to nicotinic acid which comprises reacting betapicoline with a substantially neutral to alkaline aqueous solution of an alkali metal dichromate at a temperature between about 200 and about 250 C. and under a superatmospheric pressure equivalent to the vapor pressure of the reacting mixture at the temperature employed, separating the insoluble chromic oxide formed by the reaction from the remainder of the reaction mixture, and recovering nicotinic acid from said reaction mixture.

5. A process for the production of nicotinic acid which comprises reacting beta-picoline with.

a substantially neutral to alkaline aqueous solution of a water-soluble hexavalent chromium compound at a temperature between about 200 and about 250 C. and under a superatmospheric pressure equivalent to the vapor pressure of the reacting mixture at the temperature employed, separating the insoluble chromic oxide formed by the oxidation from the remainder of the reaction mass; then reducing the pH value of the reaction mixture to between about 3 and about 4, and cooling to eiTect crystallization of nicotinic acid.

6. A process for the production of nicotinic acid which comprises subjecting beta-picoline to F the action of a substantially neutral to alkaline aqueous solution of an alkali metal dichromate -at a temperature between about 200 and about 250 C. and under a superatmospheric pressure equivalent to the vapor pressure of the reacting 5 mixture at the temperature employed for about seventeen hours, separating the insoluble ehromic oxide formed by the oxidation from the remain-- der of the reaction mass, removing excess chromate from the reaction mixture by reaction with a barium salt, separating excess barium there-q from by reaction with sulfuric acid, reducing the pH value of the reaction mixture to between about 8.2 and about 3.6 by addition of a, mineral acid, and cooling to eflect crystallization of nico- '1 tinic acid.

. JAMES OGILVIE.

ALVIN J. SWEET.

REFERENCES CITED The following references are or" record in the file of this patent:

STATES PATENTS OTHER. REFERENCES Huber, Ber. 3 p. 8%9-52 (1870.) Weiden, Annalen 165 1). 346-50 (1873.) 

